Field
This application relates to methods and compositions for administering pharmaceutical compositions to the ocular surface, the anterior chamber, and the posterior chamber of the eye for treating ocular diseases and disorders.
Background Information
Limitations of Current Therapies for the Eye
Currently, most ophthalmic drugs are administered in the form of eye-drops. With a single eye-drop, only about 5% of the drug administered is absorbed by ocular tissue; the rest is lost through naso-lacrimal drainage. Additionally, fast drainage of eye-drop formulations from the ocular space makes frequent administration regimens necessary. This leads to patient's incompliance due to inconvenience, leading to a lower therapeutic value of the treatment.
Most ophthalmic drugs are hydrophobic small molecules. For this reason, liquid eye-drops are typically suspensions due to the limited solubility of ophthalmic drugs in water. For drug suspensions to be bioavailable, the drug must be solubilized first in the eye prior to absorption. The fast clearance rate of fluid from the eye results in low drug absorption rates and inefficient delivery.
On the other hand, fully solubilized drug eye-drop solutions lead to spikes in drug concentration levels followed by fast clearance. This leads to possibly irritating high levels of drug followed by less than therapeutic levels of the drug.
Most commercial formulations of prostaglandins for glaucoma treatment contain a commonly used preservative, benzalkonium chloride, which has been correlated with ocular toxicity in both in-vivo and in-vitro studies, including corneal neurotoxicity. Chronic use of a preservative has been correlated with apoptosis of conjunctival cells and induction of inflammation. Thus, preservative-free strategies for glaucoma treatments should be part of the design space for future therapeutic regimens.
Historically, sustained-release delivery systems were designed to provide continuous release of a therapeutic agent to avoid the peak and trough therapeutic agent levels that occur in the aqueous humor with topical dosing. Sustained release delivery systems for front-of-the-eye ocular delivery include, e.g., viscous solutions to enhance residence time, punctal plugs, and drug-coated contact lenses. All of these systems have advantages over eye-drops and distinct disadvantages. For example, in addition to manufacturing challenges, drug-eluting contact lenses impact the vision field with inherent alterations in the visual acuity of the lens as the drug depletes, and punctal plugs require installation by a clinician.
Turning to therapy for diseases in the posterior chamber of the eye, drugs are typically injected in the vitreous, sub-tenon's, or suprachoroidal tissue space. Multiple injections into the back of the eye can increase the risk of infections and retinal detachment. Thus, sustained release systems have become the answer to the treatment of chronic ocular disorders, obviating the need for frequent injections.
Biodegradable implants and poly(lactic-co-glycolic acid) (PLGA) microspheres have been most commonly used for sustained release drug delivery. In the case of microspheres, the manufacturing process generates microspheres which have a size distribution. Depending upon the process, the size distribution of the delivery system can vary widely, resulting in wide variations in drug release. Wide size distributions can result in a release rate that is not precise or predictable, since the rate of diffusion of a drug through a matrix is dependent upon its path length. Other factors affecting release rate are polymer composition, rate of hydration of the microsphere matrix, and erosion of the matrix due to biodegradation. Thus, matrices with smaller sizes have shorter diffusion path-lengths and faster degradation rates, leading to faster drug release.
It is difficult to achieve a constant rate of drug release per unit time for PLGA microspheres prepared by standard techniques. Typically, what is observed is a “burst” of drug followed by a “trickling” of drug from the matrices, until the matrix disintegrates completely, leading to sudden, unpredictable, and complete release of encapsulated drug, i.e., dose dumping. Dose dumping can lead to undesirable and unanticipated side effects due to drug toxicity. Tighter control of microsphere size has been accomplished by sieving methods, although this often leads to significant losses of encapsulated drug due to the difficulty of sieving to narrow particle size ranges.
Additionally, microspheres tend to aggregate into a mass when injected into a tissue, also leading to unpredictable drug release rates. This is a major issue, since the aggregated microspheres behave like a much larger delivery system, having drug release rates dependent on the dimensions and characteristics of the aggregations. Since the shape and internal characteristic of the aggregates is unpredictable and can vary with each injection, the rate of release of the drug will vary with each administration. This leads to variability and unpredictability of drug pharmacokinetics.
As mentioned above, if drug levels are too low, the drug is ineffective and if the drug levels are too high, toxicity can result. Thus, in addition to precise and predictable drug release, a critical need exists to keep the dosage form of microspheres in a dispersed state after in-vivo administration in order to ensure consistency in drug bioavailability.
Related Art
U.S. Pat. No. 8,409,606 describes a medical prosthesis for blocking or reducing tear flow through a tear duct of a human eye while delivering a drug to the eye. The prosthesis contains a dehydrated, cross-linked synthetic hydrophilic polymer containing a therapeutic agent. The prosthesis is sized to be readily inserted into the patient's tear duct and quickly swells upon insertion to at least 1 mm in cross-sectional width to conformably fit the canaliculus into which it is inserted. The prosthesis requires a specialized instrument to allow a doctor to insert it into the eye of the patient.
U.S. Patent Application Publication 2013/0090612 describes devices which are designed to rest on the surface of the eye out of the field of vision but surrounding the cornea along at least a portion of conjunctival sac of the upper and lower lids of the eye. The devices have reservoirs containing eye medications. Some of the devices described in the application are completely non-bioerodible and others partially bioerodible.
International Patent Application Publication WO/2011/091205 describes intracameral implants including at least one therapeutic agent for treatment of an ocular condition. The implants are not anchored to the ocular tissue, but rather are held in place by currents and gravity present in the anterior chamber of an eye. The polymeric, biodegradable implants described provide sustained release of at least one therapeutic agent to both the trabecular meshwork and associated ocular tissue and the fluids within the anterior chamber of an eye. The intracameral implants must be injected by a clinician and cannot be removed if unanticipated adverse effects occur without additional surgical intervention.
U.S. Patent Application Publication 2012/0276186 describes a sustained release, biodegradable polyethylene glycol (PEG) intraocular latanoprost implant for reducing elevated intraocular pressure. The implant can be configured as a film about 100 μm to about 500 μm thick and about 2 to about 6 mm in diameter when unrolled, or an extruded filament with a diameter between about 500 μm to 1.5 mm and a length between about 5 μm to about 10 mm. Either implant is inserted into the eye of an individual via a needle to provide for extended release of latanoprost for at least 30 days. The implant requires a doctor to put it in place and it cannot be easily removed in the event of an allergic reaction.
U.S. Patent Application Publication 2004/0241207 describes a contact lens with embedded drug nanoparticles having a particle size less than about 200 nm. The embedded drug is capable of diffusion into and migration through the contact lens and into the post-lens tear film when the contact lens is placed on the eye. The technology has significant challenges both in manufacturing and maintaining the refractive power of the lenses due to light deflection occurring as a result of embedded drug particles.